Phospholipids, which are an integral component of cell membranes, exhibit a rich variety of lamellar phases modulated by temperature and composition. Molecular dynamics (MD) simulations have greatly enhanced our understanding of phospholipid membranes by capturing experimentally observed phases and phase transitions at molecular resolution. However, the ripple membrane phase, observed as an intermediate phase below the main gel-to-liquid crystalline transition with some lipids, has been challenging to capture with MD simulations, both at all-atom and coarse-grained (CG) resolution. Here, with an aggregate ~2.5 μs all-atom and ~122 μs CG MD simulations, we systematically assess the ability of six CG MARTINI 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid and water force-field (FF) variants, parametrized to capture the DPPC gel and fluid phases, for their ability to capture the ripple phase, and compared observations with those from an all-atom FF. Upon cooling from the fluid phase to below the phase transition temperature with smaller (380-lipid) and larger (> 2200-lipid) MARTINI and all-atom (CHARMM36 FF) DPPC lipid bilayers, we observed that smaller bilayers with both all-atom and MARTINI FFs sampled interdigitated ripple and ripple-like states, respectively. However, while all-atom simulations of the larger DPPC membranes exhibited the formation of the ripple phase, similar to previous studies, MARTINI membranes did not sample interdigitated ripple-like states at larger system sizes. We then demonstrated that the ripple-like states in smaller MARTINI membranes were kinetically-trapped structures caused by finite size effects rather than being representative of true ripple phases. We showed that even a MARTINI FF variant that could capture the tilted gel phase, a prerequisite for stabilizing the ripple phase, could not capture the rippled phase upon cooling. Our study reveals that the current MARTINI FFs (including MARTINI3) may require specific re-parametrization of the interaction potentials to stabilize lipid interdigitation, a characteristic of the ripple phase.

中文翻译：

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评估粗粒MARTINI力场以捕获脂质膜的波纹相

磷脂是细胞膜不可或缺的组成部分，表现出多种受温度和组成调节的层状相。分子动力学（MD）模拟通过以分子分辨率捕获实验观察到的相和相变，大大增强了我们对磷脂膜的理解。然而，波纹膜相是在凝胶和液晶之间的主要转变，并带有一些脂质的中间相，在全原子和粗粒度（CG）分辨率下，通过MD模拟很难捕获。在这里，通过约2.5μs的全原子和约122μs的CG MD模拟，我们系统地评估了六个CG MARTINI 1,2-二棕榈酰-sn-甘油-3-磷酸胆碱（DPPC）脂质和水力场的能力（FF）变体，将其参数化以捕获DPPC凝胶相和液相，以捕获波纹相，并与全原子FF的观察结果进行比较。从较小的（380-脂质）和较大的（> 2200-脂质）MARTINI和全原子（CHARMM36 FF）DPPC脂质双层从液相冷却到相变温度以下时，我们观察到同时具有全原子的较小双层和MARTINI FF分别采样了叉指纹波和类似纹波的状态。然而，尽管较大的DPPC膜的全原子模拟显示出波纹相的形成，但与先前的研究相似，MARTINI膜并未在较大的系统尺寸下采样叉指状的波纹状状态。然后，我们证明了较小的MARTINI膜中的波纹状状态是由有限尺寸效应引起的动力学陷阱结构，而不是代表真正的波纹相。我们表明，即使是可以捕获倾斜凝胶相（稳定波纹相的先决条件）的MARTINI FF变体，也无法在冷却时捕获波纹相。我们的研究表明，当前的MARTINI FF（包括MARTINI3）可能需要对相互作用电位进行特定的重新参数化才能稳定脂质互指（波纹相的一个特征）。